The present invention is a pharmaceutical composition and method for coadministration of a uricosuric agent and the like, such as probenecid or sulfinpyrazone and an excitatory amino acid (EAA) antagonist, including, for example, an AMPA antagonist, a strychnine insensitive glycine antagonist, or a competitive NMDA antagonist. This invention results in a significant increase in the duration of action and magnitude of effect for such EAA antagonists.
Numerous excitatory amino acid antagonists have been described which potently inhibit the activation of both N-methyl-D-aspartate (NMDA) and AMPA and kainic acid receptor associated ion channels in vitro. However, in vivo activity in a range of pharmacological models has often been shown to be significantly less than expected from a knowledge of the in vitro receptor binding profile. This diminished in vivo activity is thought to result from limited access of these compounds to the brain resulting from an inability to pass passively through the blood brain barrier (BBB). Poor blood brain barrier permeability has often been observed or inferred for polar or hydrophilic compounds (see, for example, R. P. Compton, et al, in Neuroscience Letters 84:339-344 (1988) and A. G. Chapman, et al, in Neuroscience Letters 37:75-80 (1983). However, in addition to an inability to cross the blood brain barrier, the inability to establish a sufficient concentration of a pharmacological agent in the brain may also result from the existence of unidirectional transport systems which are known to exist in the luminal wall of the endothelial cells which comprise the blood brain barrier. See R. Spector, in Pharmacology 40:1-7 (1990). The suggested endogenous function of such transport systems is to remove unwanted biological molecules and metabolic byproducts from the cerebrospinal fluid surrounding the brain. However, in the case of a desirable pharmacological agent, such transport systems may instead act to limit inappropriately the access of such compounds into the brain. The result of this situation is that to achieve sufficient brain concentrations of such pharmacological agents necessary for the desired pharmacological effect to be observed, compounds are required to be given in higher doses and at more frequent intervals. This increased brain penetration is often achieved through elevating serum drug concentrations to the point where significant peripheral side effects or organ toxicity are evident. Compounds which would act to inhibit the operation of such unidirectional brain endothelial transport systems would therefore be predicted to reduce the amount of a pharmacological agent required to elicit a pharmacological effect in addition to prolonging its duration of action. Such a reduction in required dosing would, of course, minimize the occurrence of peripheral side effects and limit specific organ toxicity.
Much is known about the effects; such as on renal excretion, of uricosuric drugs (see Gutman, "Uricosuric Drugs, with Special Reference to Probenecid and Sulfinpyrazone", Advances in Pharmacology 4:91-142 (1966)) and particularly probenecid (see Beyer, "Factors Basic to the Development of Useful Inhibitors of Renal Transport Mechanisms," Arch. Int. Pharmacodyn. XCVII(1):97-117 (1954); Weiner, et al, "On the Mechanism of Action of Probenecid on Renal Tubular Secretion," Bull. Johns Hopkins Hospital 156:333-346 (1960); Hedaya, et al, "Probenecid Inhibits the Metabolic and Renal Clearances of Zidorudine (AZT) in Human Volunteers", Pharmac. Res. 7(4):411-417 (1990), and "Probenecid", Goodman and Gilman, 8th ed. pp 745-746).
In fact, generally, Cunningham, et al, in "Clinical Pharmacokinetics of Probenecid", Clinical Pharmacokinetics 6:135-151 (1981) stated "Most of the drug-drug interactions involving probenecid are due to an effect on the kidney block of transport of acidic drugs."
As early as 1950 another effect of probenecid was recognized on paraaminosalicylic acid and penicillin (see Boger, et al, "The Influence of a New Benzoic Acid Derivative of the Metabolism of Paraaminosalicylic Acid (PAS) and Penicillin" as presented before the 31st Annual Session of the American College of Physicians, Boston, April, 1950). Other disclosures of the effects of probenecid are found as follows:
Gibaldi, et al, "Apparent Effect of Probenecid on the Distribution of Penicillins in Man", Clinical Pharmacology and Therapeutics 9(3):345-349; Dewhurst, K., "The Use of Probenecid for Increasing Penicillin Concentrations in Cerebro-Spinal Fluid", Acta Neurol. Scandinav. 45:253-256 (1969); Sjostrom, R., "Steady-State Levels of Probenecid and Their Relation to Acid Monamine Metabolites in Human Cerebrospinal Fluid", Psychopharmacologia (Berl.) 25:96-100 (1972). PA1 Spector, R. and Lorenzo, A. V., "The Effects of Salicylate and Probenecid on the Cerebrospinal Fluid Transport of Penicillin, Aminosalicylic Acid and Iodide", The Journal of Pharmacology and Experimental Therapeutics 1988(1):55-65 (1974); Roos, et al, "Quantitation of CSF Concentrations and Biological Activity of Probenecid Metabolites", Eur. J. Clin. Pharmacol. 17:223-226 (1980); Van Der Poel, F. W., et al, "Evidence for a Probenecid-Sensitive Transport System of Acid Monoamine Metabolites from the Spinal Subarachnoid Space", Psychopharmacology 52:35-40 (1977); Bode, et al, "Active Transport of Methotrexate from Cerebrospinal Fluid in Humans", Cancer Research 40:2184-2187 (July 1980); Hedaya, M. A. and Sawchuk, R. J., "Effect of Probenecid on the Renal and Nonrenal Clearances of Zidovudine and its Distribution into Cerebrospinal Fluid in the Rabbit, J. of Pharmaceutical Sciences 78(9):716-22 (September 1989); Sawchuk, R. J. and Hedaya, M. A., "Modeling the Enhanced Uptake of Zidovudine (AZT) into Cerebrospinal Fluid. I. Effect of Probenecid, Pharmaceutical Research 7(4):332-338 (1990).
Studies regarding excitatory amino acid antagonist pharmacokinetics provide no basis to lead an ordinary artisan to the differences of the present invention. See Chapman, et al, "Uptake of a Novel Anticonvulsant Compound, 2-Amino-7-Phosphono-4,5-.sup.3 H!Heptanoic Acid, into Mouse Brain", Neuroscience Letters 37:75-80 (1983) and Compton, et al, "Determination of the Pharmacokinetics of 2-Amino-7-Phosphonoheptanoate in Rat Plasma and Cerebrospinal Fluid", Neuroscience Letters 84:339-344 (1988).
Specifically, I. McDonald of Merrell-Dow presented a talk at the Excitatory Amino Acid Symposium held at the American Chemical Society Spring National Meeting held in Atlanta, Ga. on Apr. 15, 1991 in which he stated that preliminary metabolic studies show longer duration of protection against seizures induced by quinolinic acid in mice when pretreated with probenecid followed by the administration of a compound of the formula 4-(carboxymethyl)imino!-5,7-dichloro-1,4-dihydro-2-quinolinecarboxylic acid (MDL 100,748), This was shown by the following data: